This proposal stems from 15 years of research on S. haematobium infection in Coast Province, Kenya that have served to challenge the traditional concept of the relationship among treatment, infection and morbidity. For S. haematobium, as well as other helminth infections, infection intensity before treatment shows significant person-to person, family-to-family and village-to- village variation. In treated populations in Kenya, our long follow-up period has permitted observation of reduced infection intensity and reduced acute morbidity among schoolchildren, but the development of hydronephrosis among many in adulthood. Thus, for early infection and disease as well as morbidity later in life, the heterogeneity of worm burden and disease outcome is not adequately explained by differences in parasite exposure. Increasing evidence suggests that the aggregated distributions of infection and disease is due in significant part to differences in environmental factors, genetically based differences in human biology or by specific immunologic mechanisms in some hosts. This single-project ICIDR represents a systematic evaluation of the major sources for variation in human susceptibility to disease and morbidity. Since characteristics of the disease itself are age dependent, factors will be sought from pre-exposed children, children demonstrating early forms of disease and adults presenting with late disease will be specifically targeted. Epidemiologic, demographic, parasitologic and sociologic factors will be quantified and analyzed for associations. These quantified risk factors will in turn be used to analyze familial segregation of phenotypes, as well as linkage between genetic markers and susceptibility. The effect of pre- natal exposure to schistosome antigens and childhood TNFalpha and TGFbeta production in lymphocytes will be specifically analyzed for their contribution to the observed variability in infection and outcome. Epidemiologic factors will be evaluated in Specific Aim 1 by cross-sectional and prospective studies that will evaluate and quantify the impact of age, sex, cultural and socio- economic background, intensity of infection and water contact. These studies will provide estimates of risk variables that will be used for genetic studies in Specific Aim 2. Specific Aim 3 will examine neonates and infants for the effect of prenatal exposure on outcome and the expression of the cytokines TNFalpha and TGFbeta in school-aged children. This information, combined with epidemiological modeling of control strategies, will allow accelerated synthesis of the next generation of control programs.